What every physician needs to know:

Chronic mediastinitis results from an inflammatory reaction of the mediastinal lymph nodes, usually in response to prior Histoplasma capsulatum infection. Chronic mediastinitis can manifest as a mediastinal granuloma or, less commonly, as fibrosing mediastinitis. Fibrosing mediastinitis is a mass-like fibrotic reaction that can compress mediastinal structures like the tracheobronchial tree, great vessel. Erosion into blood vessels can cause hemoptysis and compression of major vessels can have congestive consequences, such as superior vena cava (SVC) syndrome or pulmonary edema. Medical management is often ineffective in reversing the process and mostly aimed at preventing progression or enlargement of the fibrotic nodal mass. Resection is often not feasible and surgical intervention is reserved for diagnosis and palliation.

Classification:

Chronic forms of mediastinitis include mediastinal granulomas and fibrosing mediastinitis. Mediastinal granuloma, the more common process, presents as an encapsulated mass of coalesced lymph nodes, generally caused by autoimmune disease or microbes (bacteria such as actinomyces and nocardia, fungus such as Histoplasma or Cryptococcus, or acid-fast bacilli). Fibrosing mediastinitis results from an extensive hypersensitivity response to instigating triggers and may be associated with Ig-G4-related disease. Cases of fibrosing mediastinitis can be further subdivided into two patterns of distribution: diffuse and focal. The most common presentation is the development of focal lesions involving the right paratracheal and subcarinal regions.

Are you sure your patient has chronic mediastinitis? What should you expect to find?

The hallmark feature of fibrosing mediastinitis is the presence of dense fibrotic tissue in the mediastinum, which may appear radiographically as a large mass. Although this represents a benign process, it is still an aggressive one and symptoms due to mass-effect may result. Compression of the airway, esophagus, or major vessels will precipitate relevant symptoms. Central airway compression can cause dyspnea, atelectasis, and recurrent or post-obstructive pneumonia. Calcified nodes in the granulomata can erode into the bronchial wall, resulting in broncholithiasis, obstructive symptoms, and/or hemoptysis. Symptoms from esophageal involvement may include dysphagia, odynophagia, or aspiration/recurrent infection if an esophageal fistula develops to the airway.

Mass-effect on the SVC can cause SVC syndrome, which manifests as edema of the face, arms, and neck. Some reports attribute a higher rate of SVC syndrome to mediastinal granulomas. Symptoms resulting from involvement of the pulmonary vessels include progressive or exertional dyspnea and hemoptysis. Chronic occlusion of pulmonary veins can result in secondary pulmonary arterial hypertension and cor pulmonale. Hemoptysis can result from involvement of the airway mucosa, erosion into blood vessels, or pulmonary hypertension from obstruction of pulmonary vessels. Other less common symptoms are fever and weight loss.

Beware: there are other diseases that can mimic chronic mediastinitis.

Other diagnoses that may have a similar radiographic presentation include malignancies like small-cell lung cancer, lymphoma, and germ cell tumors. Fungal or mycobacterial infections, sarcoidosis, silicosis, and paraffin (late sequelae of tuberculosis plombage) can also mimic chronic mediastinitis.

Biopsy proven fibrosis in the mediastinal space can also occur with sclerosing non-Hodgkins lymphoma, Hodgkins lymphoma (nodular sclerosis), spindle cell tumors, thymoma, thymic carcinoid, simple fibrosis, fibromatosis, and low-grade sarcoma. Needle biopsy may not be adequate to exclude these other diagnoses and therefore, surgical biopsy with extensive tissue sampling and pathology evaluation may be needed to differentiate between chronic mediastinitis and other causes of mediastinal fibrosis.

How and/or why did the patient develop chronic mediastinitis?

The exact cause of chronic mediastinitis is unclear and is almost never linked to the chronic effect of an acute suppurative infection. Fibrosing mediastinitis is thought to be the consequence of a hypersensitivity immune response, resulting in abnormal proliferation of dense acellular collagen and fibrous tissue within the mediastinum. Fibrosing mediastinitis is not likely to represent active infection, as organisms cannot be identified in the majority of tissue samples. The most common associated infectious agent is H. capsulatum, which is endemic to the central, southeastern, and mid-Atlantic regions of the United States.

Mycobacterium tuberculosis is a less common cause, while other fungi, autoimmune disorders, silicosis, familial multifocal fibrosclerosis, and methylsergide (a serotonin-antagonist used to treat migraines) have also been described as rare causative agents. Only a small minority of patients with mediastinal infection by causative agents develop fibrosing mediastinitis. More than 500,000 people are infected by H. capsulatum annually in the United States, and over 80 percent of people living in endemic regions are positive for the Histoplasma skin test. Less than 1 percent of patients with histoplasmosis, however, develop fibrosing mediastinitis.

There are two predominant patterns of fibrosing mediastinitis. In one large study, 83% of patients with fibrosing mediastinitis demonstrated a localized disease process mostly in the right paratracheal and subcarinal spaces. Sixty-three percent of these lesions were calcified. Patients with this presentation typically had evidence of prior histoplasmosis or tuberculosis. The remaining 18% of patients presented with a diffuse non-calcified infiltrative fibrotic process that involved multiple mediastinal compartments. Patients with the non-calcified infiltrative process had a higher incidence of other idiopathic inflammatory fibrotic processes, such as retroperitoneal fibrosis, rather than prior granulomatous disease. The differences in these two patterns of disease suggest that fibrosing mediastinitis may be comprised of two different disease processes: the predominant type (in the United States) in response to prior granulomatous infection versus a less common, more diffuse, idiopathic infiltrative process.

Mediastinal granulomas, on the other hand, are conglomerations of enlarged lymph nodes that result from direct infection by the H. capsulatum organism. These nodes are encapsulated and contain fibrous or caseating (necrotic) material.

There is some suggestion that mediastinal granuloma and fibrosing mediastinitis may represent a spectrum of disease, as one small case series describes the development of fibrosing mediastinitis in 34% of patients with mediastinal granuloma within a two-year period. However, a review of the medical literature by Loyd et al. did not support a connection between the two entities, aside from their association with prior histoplasmosis.

Which individuals are at greatest risk of developing chronic mediastinitis?

It is unclear why only a small minority of patients with histoplasmosis develop fibrosing mediastinitis. A possible association with the HLA-A2 antigen suggests that there may be a genetic component to the development of the disease.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Histoplasma antigen testing is useful in determining a patient's prior exposure to the fungus, but this test is not specific for chronic mediastinitis, as few patients with histoplasmosis develop chronic mediastinitis. Similarly, testing for other infectious agents, such as tuberculosis, is also non-specific. The role of fine-needle aspirate is limited to ruling out malignant alternative diagnoses. Biopsy (core needle or surgical) demonstrates characteristic findings of collagen deposition, fibrosis, and possible granulomas.

What imaging studies will be helpful in making or excluding the diagnosis of chronic mediastinitis?

Computed tomography (CT) of the chest with contrast is helpful in delineating mediastinal structures, including soft tissue abnormalities and relationships with vessels. Magnetic resonance imaging (MRI) can also be used to evaluate mediastinal structures. Chest x-ray (CXR) is non-specific, and most commonly demonstrates enlargement of the mediastinum and lymphadenopathy in the subcarinal, right paratracheal, and right hilar regions. Calcifications are seen in up to 86% of cases. Other possible radiographic findings include vascular congestion related to obstruction of the SVC or pulmonary vessels, parenchymal infiltrates/atelectasis, and narrowing of the large airways from central airway obstruction.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of chronic mediastinitis?

Chronic fibrosing mediastinitis is suggested in patients with the right clinical history and radiographic findings consistent with the disease. The lack of calcifications increases the likelihood of other diagnoses, however. In addition, tissue sampling is often necessary to exclude other differential diagnoses such as malignancy, sarcoidosis, or infections, as radiographic findings are non-specific.

What diagnostic procedures will be helpful in making or excluding the diagnosis of chronic mediastinitis?

Tissue biopsy is necessary for diagnosis of the disease and exclusion of other diagnoses. Mediastinal granulomas will demonstrate caseating granulomas on histology, while fibrosing mediastinitis will demonstrate an exuberant dense fibrosis, with plasma cells and lymphocytes, hyalinized collagen, and sometimes granulomas encasing mediastinal structures.

Endoscopic biopsy (bronchoscopy or EGD) can be used to obtain fine-needle aspirates and sometimes core samples, often utilizing ultrasound guidance techniques. Although small tissue samples limited by the gauge of the endoscopic biopsy needle may limit pathology interpretation, these endoscopic biopsies are useful in excluding malignancy and active infections.

Large tissue samples are typically required to make the diagnosis of fibrosing mediastinitis and to rule out diseases with similar presentations. Extensive diagnostic tissue sampling can be obtained via mediastinoscopy (cervical and anterior), video-assisted thoracoscopic surgery (VATS), or thoracotomy. Care should be taken since associated pulmonary hypertension increases the risk of hemorrhage with biopsies involving the lung.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of chronic mediastinitis?

Tissue specimens demonstrate an infiltrating, fibrotic process. One classification system divides pathology findings into three categories. These histologic groups are only descriptive and have not been shown to be predictive of clinical outcomes:

Stage I: predominance of edematous fibromyxoid tissue

Stage II: presence of eosinophilic hyaline material that forms a glassy band that surrounds and infiltrates mediastinal structures

Stage III: dense pauci-cellular collagen that obliterates other structures, which is the classic microscopic feature of fibrosing mediastinitis

Pathologic evaluation is also helpful in excluding other possible differential diagnoses. Spindle cell tumors (for example, localized fibrous tumors of the pleura or diffuse desmoplastic malignant pleural mesothelioma) demonstrate more cellularity than do samples in fibrosing mediastinitis. CD34 and bcl-2 staining for localized fibrous tumors of the pleura and keratin staining for epithelial tumors such as mesothelioma are also useful. Metastatic carcinomas, thymic carcinoid, and thymoma are also positive for keratin stain.

If you decide the patient has chronic mediastinitis, how should the patient be managed?

Treatment is largely based on palliating symptoms. Surgical intervention can be considered for mediastinal granulomas that are symptomatic due to mass-effect on mediastinal structures and these granulomas are resectable. Calcified broncholiths that erode into the tracheobronchial tree should not be removed bronchoscopically because of the risk of catastrophic bleeding after they are removed from the airway wall.

In fibrosing mediastinitis, only case reports or small series have described the use of antifungal agents, and the paucity of data limits recommendations for a standard approach using these agents. Most studies did not support use of glucocorticoids, despite the theory that this process stems from an aggressive fibrotic immune response. Given the high level of morbidity associated with surgical intervention, localized therapeutic interventions are now used for relief of symptoms: bypass vein grafts and endovascular grafts can alleviate SVC syndrome, therapeutic bronchoscopic dilation and stenting are used for airway obstruction, and surgical closure or stenting can be performed for tracheoesophageal fistulas or esophageal compression.

What is the prognosis for patients managed in the recommended ways?

Chronic granulomas are often benign and usually do not cause mortality. However, fibrosing mediastinitis is a chronic and potentially progressive process; several small case series described >30% mortality within six years of onset of symptoms, despite therapy. Mortality is typically related to complications from hemoptysis, recurrent infections, or cor pulmonale.

What other considerations exist for patients with chronic mediastinitis?

Primary considerations for the diagnosis and treatment of the disease have been outlined above.

(Review of the history, presentation, pathology, diagnosis, and treatment of chronic mediastinitis.)**The original authors for this chapter were Drs. Ali Musani and David Hsia. The chapter was revised by Drs. Julian Horwitz and Andrea Wolf.